下丘脑前核:参与褪黑素对血压影响的中枢部位

在大鼠用微量注射技术研究褪黑素在下丘脑前核对心血管活动的作用,以及用辣根过氧化物酶神经传导通路追踪技术研究下丘脑前核参与心血管活动交感传出的纤维投射.结果表明,下丘脑前核微量注射褪黑素可使血压呈剂量依赖性降低,下丘脑前核有大量纤维投射到室旁核、正中隆起、下丘脑腹内侧核、弓状核、中脑导水管周围灰质,有少量纤维投射到延髓腹外侧区、中缝隐核.因此,褪黑素可能为一种降压因子,下丘脑前核是褪黑素调节心血管活动的重要中枢部位之一,而且下丘脑前核可能通过下丘脑腹内侧核、弓状核、中脑导水管周围灰质、延髓腹外侧区和中缝隐核来影响心血管交感传出活动.     

下丘脑前核：参与褪黑素对血压影响的中枢部位

在大鼠用微量注射技术研究褪黑素在下丘脑前核对心血管活动的作用 ,以及用辣根过氧化物酶神经传导通路追踪技术研究下丘脑前核参与心血管活动交感传出的纤维投射。结果表明 ,下丘脑前核微量注射褪黑素可使血压呈剂量依赖性降低 ,下丘脑前核有大量纤维投射到室旁核、正中隆起、下丘脑腹内侧核、弓状核、中脑导水管周围灰质 ,有少量纤维投射到延髓腹外侧区、中缝隐核。因此 ,褪黑素可能为一种降压因子 ,下丘脑前核是褪黑素调节心血管活动的重要中枢部位之一 ,而且下丘脑前核可能通过下丘脑腹内侧核、弓状核、中脑导水管周围灰质、延髓腹外侧区和中缝隐核来影响心血管交感传出活动     

Morphologic evidence for intranuclear circuits in the hypothalamic arcuate nucleus

Three weeks after complete deafferentation of the medial basal hypothalamus (MBH) of adult female rats, the hypothalamic arcuate nucleus (ARCN) was examined ultrastructurally. Axodendritic and axosomatic synapses were counted in a field of 18,000 μm² in the middle part of the ARCN in each brain. Intraventricular infusion of 5-hydroxydopamine before autopsy resulted in the differentiation of two types of axon terminals. One axon terminal contained small spherical vesicles (SSVs, about 50 nm in diameter) and the other contained 5-hydroxydopamine-labeled small granular vesicles (SGVs) which were regarded as monoaminergic terminals. In the completely deafferented MBH, mean numbers of SSV and SGV synapses of the ARCN decreased to about one-half and one-fourth, respectively, compared to those of the unoperated rats. However, considerable numbers of intact SSV and SGV synapses were still encountered in the ARCN following deafferentation. There was no significant difference in the number of synapses between the large MBH island (including ARCN and ventromedial nucleus) and the small MBH island (mostly localized in ARCN). These results suggested that numerous converging nonmonoaminergic and monoaminergic fibers terminated in the ARCN and also suggested that nonmonoaminergic and monoaminergic arcuate neurons connected directly with other arcuate neurons.     

Candidate genes involved in neural plasticity and the risk for attention-deficit hyperactivity disorder: a meta-analysis of 8 common variants

Background

Attention-deficit hyperactivity disorder (ADHD) is an important psychiatric condition in terms of its prevalence and impact on quality of life. It has one of the highest heritabilities found in psychiatric disorders. A number of association studies exploring several candidate genes in different populations around the world have been carried out. The objective of the present study was to carry out a meta-analysis for 8 common variants located in 5 top candidate genes for ADHD (BDNF, HTR1B, SLC6A2, SLC6A4 and SNAP25); these genes are known to be involved in synaptic transmission and plasticity.

Methods

We performed a search for published genetic association studies that analyzed the candidate polymorphisms in different populations, and we applied state-of-the-art meta-analytical procedures to obtain pooled odds ratios (ORs) and to evaluate potential basis of heterogeneity. We included 75 genetic association studies in these meta-analyses.

Results

A major part of the previously postulated associations were nonconsistent in the pooled odds ratios. We observed a weak significant association with a single nucleotide polymorphism (SNP) located in the 3′ UTR region of the SNAP25 gene (rs3746544, T allele, OR 1.15, 95% confidence interval 1.01–1.31, p = 0.028, I² = 0%). In addition to the low coverage of genetic variability given by these variants, phenotypic heterogeneity between samples (ADHD subtypes, comorbidities) and genetic background may explain these differences.

Limitations

Limitations of our study include the retrospective nature of our meta-analysis with the incorporation of study-level data from published articles.

Conclusion

To our knowledge, the present study is the largest meta-analysis carried out for ADHD genetics; previously proposed cumulative associations with common polymorphisms in SLC6A4 and HTR1B genes were not supported. We identified a weak consistent association with a common SNP in the SNAP25 gene, a molecule that is known to be central for synaptic transmission and plasticity mechanisms.     

Cracking neural circuits in a tiny brain: new approaches for understanding the neural circuitry of Drosophila

Genetic screens in Drosophila have identified many genes involved in neural development and function. However, until recently, it has been impossible to monitor neural signals in Drosophila central neurons, and it has been difficult to make specific perturbations to central neural circuits. This has changed in the past few years with the development of new tools for measuring and manipulating neural activity in the fly. Here we review how these new tools enable novel conceptual approaches to 'cracking circuits' in this important model organism. We discuss recent studies aimed at defining the cognitive demands on the fly brain, identifying the cellular components of specific neural circuits, mapping functional connectivity in those circuits and defining causal relationships between neural activity and behavior.     

Cholecystokinin induces c-fos expression in hypothalamic oxytocinergic neurons projecting to the dorsal vagal complex.

Systemic administration of cholecystokinin (CCK) decreases gastric motility and stimulates pituitary secretion of oxytocin (OT). Although peripheral OT does not affect gastric function, increasing evidence suggests that central OT secretion acting within the dorsal vagal complex (DVC) can alter gastric motility. To evaluate whether systemically administered CCK is capable of activating oxytocinergic neurons projecting to the DVC, we utilized fluorogold retrograde labeling from the DVC in combination with c-fos and OT immunocytochemical staining to quantitatively analyze paraventricular nucleus (PVN) neurons of rats following injection of CCK at a dose known to cause maximal pituitary OT secretion (100 micrograms/kg i.p.). Our results showed that 2320 +/- 63 PVN neurons were retrogradely labeled from the DVC; 146 +/- 21 (6.3%) of these contained OT, and these cells were predominantly located in the medial parvocellular subdivision of the PVN. Of all retrogradely labeled cells, 671 +/- 112 (28.9%) expressed c-fos after CCK stimulation, and 68 +/- 14 of these (10.1%) contained OT. Approximately 50% of the OT-containing neurons retrogradely labeled from the DVC stained positively for c-fos. Many magnocellular OT neurons in the PVN that were not retrogradely labeled from the DVC also expressed c-fos after CCK stimulation. These results demonstrate that parvocellular OT neurons projecting to the DVC are co-activated along with magnocellular OT neurons projecting to the pituitary following administration of a large dose of CCK, and lend support to a possible functional role for OT as a central neurotransmitter that modulates vagal efferent traffic to the gastrointestinal tract.     

Corticotropin-releasing factor neurons in the hypothalamic paraventricular nucleus are involved in arousal/yawning response of rats

Our previous studies have suggested that activation of the hypothalamic paraventricular (PVN) descending oxytocinergic projections is involved in the induction of yawning accompanied by an arousal response, but the possibility that neural systems other than the oxytocinergic system in the PVN also mediate the arousal/yawning response cannot be ruled out. We assessed the activity of corticotropin-releasing factor (CRF) neurons during yawning induced by the PVN stimulation in anesthetized, spontaneously breathing rats using double-staining for c-Fos and CRF. Yawning response was evaluated by monitoring an intercostals electromyogram as an index of inspiratory activity and a digastric electromyogram as an indicator of mouth opening. We also recorded the electrocorticogram (ECoG) to determine the arousal response during yawning. Microinjection of l-glutamate (2-5 nmol) into the PVN produced a frequent yawning accompanied by an arousal shift in the ECoG, and these behavioral effects were associated with a significant increase of c-Fos positive CRF neurons in the medial parvocellular subdivision of the PVN. In addition, a marked enhancement in the c-Fos expression was found in the both locus coeruleus (LC) and global area in the cortex when the frequency of yawning response was increased by the PVN stimulation, suggesting that the arousal response during yawning might be mediated by the activation of LC neurons. The present study suggests that an activation of CRF neurons in the PVN is responsible for the arousal response accompanied by yawning behavior.     

Distinct roles for specific leptin receptor signals in the development of hypothalamic feeding circuits

Circulating hormones influence multiple aspects of hypothalamic development and play a role in directing formation of neural circuits. Leptin is secreted by adipocytes and functions as a key developmental signal that promotes axon outgrowth from the arcuate nucleus (ARH) during a discrete developmental critical period. To determine the cellular mechanisms by which leptin impacts development of hypothalamic circuits, we examined roles for leptin receptor (LepRb) signals in neonatal mice. LepRb, ERK, and STAT3 signaling were required for leptin-stimulated neurite outgrowth from ARH explants in vitro. Neonatal mice with disrupted LepRb→ERK signaling displayed impaired ARH projections but were able to compensate by adulthood. LepRb→STAT3 signaling also plays a role in early circuit formation and controls the ultimate architecture of POMC, but not AgRP, projections. Thus, the developmental actions of leptin on feeding circuits are dependent on LepRb, and distinct signaling pathways are responsible for directing formation of NPY and POMC projections.     

CNS cell groups projecting to sympathetic outflow of tail artery: neural circuits involved in heat loss in the rat

In the rat, ≈20% of total body heat-loss occurs by sympathetically mediated increases in blood flow through an elaborate system of arteriovenous anastomoses in the skin of its tail. In this study, the CNS cell groups that regulate this sympathetic outflow were identified by the viral transneuronal labeling method. Pseudorabies virus was injected into the wall of the ventral tail artery in rats that had their cauda equina transected to eliminate the somatic innervation of the tail. After 4–7 days survival, the pattern of CNS transneuronal labeling was studied. Sympathetic preganglionic neurons in the T11–L2 (mainly L1) levels of the intermediolateral cell column (IML) were labeled by 4 days. After 5 days, sympathetic pre-motor neurons (i.e., supraspinal neurons that project to the IML) were identified near the ventral medullary surface; some of these contained serotonin immunoreactivity. Additional groups of the sympathetic premotor areas were labeled by 6 days post-injection, including the rostral ventrolateral medulla (C1 adrenergic neurons), rostral ventromedial medulla, caudal raphe nuclei (serotonin neurons in the raphe pallidus and magnus nuclei), A5 noradrenergic cell group, lateral hypothalamic area and paraventricular hypothalamic area (oxytocin-immunoreactive neurons). Seven days after the PRV injections, additional cell groups in the telencephalon (viz., bed nucleus of the stria terminalis, medial and lateral preoptic areas and medial preoptic nucleus), diencephalon (viz., subincertal nucleus, zona incerta as well as dorsal, dorsomedial, parafascicular, posterior and ventromedial hypothalamic nuclei) and midbrain (viz., periaqueductal gray matter, precommissural nucleus, Edinger–Westphal nucleus and ventral tegmental area) were labeled. The discussion is focused on the CNS cell groups involved in the control of body temperature and fever.     

Expression of c-fos mRNA after cortical ablation in rat brain is modulated by basic fibroblast growth factor (bFGF) and the NMDA receptor is involved in c-fos expression

Expression of c-fos mRNA after cortical injury was studied using the in situ hybridization technique. Strong signals for c-fos mRNA were observed immediately after cortical ablation in neurons throughout the cortex ipsilateral to the injury. However, this c-fos mRNA expression was transient and disappeared within 6 h after the injury. When basic fibroblast growth factor (bFGF; 1 μg) was applied to the site of ablation, c-fos mRNA signals were observed for a much longer period. Even 24 h after injury, diffuse expression of c-fos mRNA was detected throughout the cortex, being mainly confined to non-neuronal cells. Intraperitoneal injection of MK-801 (3 mg/kg), a non-competitive NMDA receptor antagonist, suppressed the expression of c-fos mRNA after cortical ablation. It suppressed both the immediate and late expression induced by cortical ablation and bFGF. The immediate expression of c-fos in neurons is likely to be due to spreading depression, while neuronal-glial interactions would be involved in the mechanism of late c-fos expression by non-neuronal cells. Our results suggest that induction of c-fos after cortical injury can be modulated by topically applied bFGF and that the N-methyl-d-aspartate (NMDA) receptor is involved in c-fos expression not only caused by injury itself but also induced by injury and bFGF. As the immediate early genes regulate secondary gene responses, the induction of c-fos may contribute to neuronal plasticity and bFGF may enhance its effect.